The poor prognosis of patients with advanced pancreatic adenocarcinoma, with a median survival of less than 12 months, indicates an obvious need for more effective treatments. In addition, patients with pancreatic carcinoma are frequently debilitated by cachexia, anorexia, nausea/vomiting and abdominal pain. Pro-inflammatory cytokines like tumor necrosis factor (TNF) alpha, interleukin 6 (IL-6) and interleukin 1 (IL-1) have all been found to be elevated in pancreatic cancer patients and have been implicated in causing many of these symptoms, in addition to the possibility of directly promoting tumor progression. One potential target for anticancer therapy is blocking the effects of TNF. We hypothesize that TNF blockade should make chemotherapy more tolerable, should improve quality of life and should retard the time to tumor progression. In the current proposal, we seek to combine standard chemotherapy (gemcitabine) and TNF blockade with soluble TNF receptor molecules (etanercept) in a pilot trial in patients with metastatic or recurrent pancreatic cancer. We will evaluate if TNF blockade can improve the clinical benefit response, quality of life and the rate of cancer progression-free survival at six months obtained with chemotherapy. In addition, serial levels of TNF and other inflammatory cytokines, as well as the transcription factor NF-kappaB, a candidate pathway through which TNF stimulates tumor growth, will be obtained from peripheral blood mononuclear cells lysates. Quality of life and levels of the cytokines and NF-kappaB will also be measured in a control group of 10 patients receiving gemcitabine as a single agent. The observation of benefits in either quality of life or progression-free survival in patients undergoing TNF blockade would encourage evaluation of this novel strategy in properly powered randomized clinical trials.